The role of adipokines in glucose regulation and metabolic decline Project Abstract: Type 2 diabetes mellitus (T2DM) develops from progressive loss of pancreatic ?-cell compensation for chronic insulin resistance. The loss of compensation occurs for years prior to the development of T2DM, and is due to reduction in ?-cell mass and deterioration of ?-cell function. Obesity is an important cause of ?-cell dysfunction in T2DM. The proposed work is designed to expand our understanding of the impact of adipokines, a metabolic product of adipose tissue, on glucose regulation and metabolic decline. Previous studies of adipokine associations with metabolic traits have been limited by use of only surrogate measures of insulin resistance and ?-cell function, lack of key data on genes and environment, and/or small sample size. Few have examined the longitudinal effects of changes in adipokines over time. Our primary hypothesis is that the imbalance in pro- and anti-inflammatory adipokine levels driven by obesity contributes to the ?-cell decline that eventually leads to hyperglycemia and T2DM. Specifically, we believe that pro-inflammatory adipokines promote and anti-inflammatory adipokines protect against insulin resistance and ?-cell dysfunction. We will leverage the unique resources of the BetaGene cross-sectional (NIDDK R01 DK061628) and ongoing follow- up (NIDDK 2R01 DK061628) studies to test our hypothesis. The BetaGene cohort consists of Mexican American families ascertained through probands with or without a recent history of GDM. Cross-sectional (n=1,247) and longitudinal (n=390; median follow-up ~4.2 years) data includes detailed phenotyping for body composition, glucose metabolism, insulin sensitivity and ?-cell function (DXA, OGTT, FSIGT); diet and physical activity assessments, and genome-wide genotyping. As such, BetaGene includes a vast array of sophisticated phenotype, genotype and lifestyle data in a large cohort of Mexican Americans, which uniquely enables us to examine the complex pathways that underlie the pathogenesis of T2DM. We propose to measure a large panel of adipokines using stored specimens from the BetaGene cohort, and combine with existing phenotype, genotype and lifestyle data, to achieve the following Specific Aims: (1) to investigate the extent to which obesity and weight gain contribute to higher levels of pro-inflammatory and lower levels of anti- inflammatory adipokines, and their increases or decreases over time, (2) to assess the effect of this adipokine imbalance on insulin sensitivity, and (3) to determine the extent to which adipokine dysregulation directly and indirectly effects ?-cell function, and the degree to which these effects are explained by obesity and insulin resistance. We will also leverage existing genetic and lifestyle data to explore the potential modifying effects of variation in obesity- and T2DM-risk genes, diet and physical activity. With the completion of these aims, we will provide valuable new information on the complex role of adipokines in glucose regulation and metabolic decline, with the long-term goal of developing targeted interventions to mitigate the adverse metabolic effects of obesity, preserve or restore ?-cell function, and thus prevent or treat T2DM.